The field of the invention is electrical property imaging systems and methods. More particularly, the invention relates to characterizing an anomaly in a tissue as pre-cancerous, cancerous, or non-cancerous.
Screening mammography has been the gold standard for breast cancer detection for over 30 years, and is the only available screening method proven to reduce breast cancer mortality. As a result, breast cancer mortality has decreased 25% since 1990. However, the sensitivity of screening mammography varies considerably. For example, the false-negative rate for mammography is around 20% and the false-positive rate around 12%. Moreover, radiologists cannot distinguish malignant and benign breast tissue by viewing a mammogram.
The most important factor in the failure of mammography to detect breast cancer is radiographic breast density. In studies examining the sensitivity of mammography as a function of breast density, the sensitivity of mammography falls from around 85% in women with fatty breasts to 48-63% in women with extremely dense breasts. Additional drawbacks of conventional mammographic screening include patient discomfort associated with the compression of the breast (mammography requires 45 pounds of pressure).
Screening alternatives to mammography include ultrasound and MRI. The effectiveness of whole-breast ultrasound as a screening technique, however, does not appear to be significantly different from mammography. Furthermore, while MRI has appreciable sensitivity for the detection for breast cancer and is not affected by breast density, the high cost of bilateral breast MRI (approximately 10 times more expensive than mammography) has precluded its widespread use as a screening technique. Other issues limiting the widespread use of MRI as a screening tool for breast cancer include the variability of the equipment involved, the long scan times often required for imaging session, the lack of clarity regarding the preferred imaging technique and result interpretation criteria, and its relative inability to reliably detect microcalcifications and DCIS. Furthermore, MRI has a higher false-positive rate compared to conventional mammography and performs poorly for detecting invasive lobular cancers.
A high percentage of breast cancers are not detected at the screening stage as standard mammographic images are one of the most difficult radiographic exams to interpret. Studies show that 20% to 50% of breast cancers go undetected at the screening stage. The motivation for early detection is great. For example, breast cancer detected in the early stage has an average cost of treatment of $11,000 and a 5 year survival rate of approximately 96%, while late stage breast cancer costs $140,000 on average to treat and the 5 year survival falls to 20%. Moreover, 5% of breast cancer tumors appear to double in size in just over a month.
After a suspicious lesion is found, medical professionals often rely on expensive biopsies to diagnose cancerous tissues. These procedures are neither fast nor patient-friendly. Surgical biopsy is recommended for suspicious lesions with a high chance of malignancy but fine-needle aspiration cytology (FNAC) and core biopsy can be inexpensive and effective alternatives. Both FNAC and core biopsy have helped to reduce the number of surgical biopsies, sparing patients anxiety and reducing the cost of the procedure. However, core biopsies have often failed to show invasive carcinoma and both FNAC and core biopsies can result in the displacement of malignant cells away from the target, resulting in misdiagnosis. Additionally, core biopsies have a limited sampling accuracy because only a few small pieces of tissue are extracted from random locations in the suspicious mass. In some cases, sampling of the suspicious mass maybe missed altogether. Consequences include a false-negative rate of 1-7% (when verified with follow up mammography) and repeat biopsies (percutaneous or surgical) in 9-18% of patients due to discordance between histological findings and mammography. The sampling accuracy of core needle biopsy is, furthermore, highly dependent on operator skills and on the equipment used.
Less invasive methods of diagnosing breast cancer, such as needle biopsy and sentinel node biopsy, can largely replace traditional open procedures, which still account for about one-third of the 1.7 million breast biopsies performed each year in the U.S. In a review of cytologic-histologic specimen pairs, errors in cancer diagnosis were seen in up to 11.8% of cases. In a substantial proportion of cases, the error caused some degree of harm for the patient. More specifically, up to 45% of errors resulted in harm to the patient, ranging from further unnecessary noninvasive diagnostic tests to loss of life or limb while up to 50% were due to pathologic misinterpretation. In the remainder of the cases, the errors were due to poor tissue sampling.
The biochemical properties of cancerous cells versus normal cells are characterized by three factors: increased intracellular content of sodium, potassium, and other ions; increased intracellular content of water; and a marked difference in the electrochemical properties of the cell membranes. The increased intracellular concentrations of sodium, potassium, and other ions result in higher intracellular electrical conductivity. Likewise, the increased water content results in higher conductivity when fatty cells surround the cancerous cells, since water is a better conductor than fat. In addition, the biochemical differences in the cell membranes of cancerous cells result in greater electrical permittivity.
A study of breast carcinoma described three separate classifications of tissue: tumor bulk, infiltrating margins, and distant (normal) tissue. The center of the lesion is called the tumor bulk and it is characterized by a high percentage of collagen, elastic fibers, and many tumor cells. Few tumor cells and a large proportion of normally distributed collagen and fat in unaffected breast tissue characterize the infiltrating margins. Finally, the distant tissues (2 cm or more from the lesion) are characterized as normal tissue.
The characterization of cancerous tissue is divided into two groups: in situ and infiltrating lesions. In situ lesions are tumors that remain confined in epithelial tissue from which they originated. The tumor does not cross the basal membrane, thus the tumor and the healthy tissue are of the same nature (epithelial). The electrical impedance of an in situ lesion is thus dependent on the abundance of the malignant cells that will impact the macroscopic conductivity (which is influenced by the increase in sodium and water) and permittivity (which is influenced by the difference in cell membrane electrochemistry).
By contrast, infiltrating lesions are tumors that pass through the basal membrane. The malignant tissue has a different nature than normal tissue (epithelial vs. adipose). Epithelial tissue is compact and dense. Adipose tissue is composed of large cells that are mostly triglycerides. These structural differences have the following impact. First, the normal tissue has a lower cellular density. Second, cell liquid of normal tissue is not as abundant as epithelial cells. Generally the radiuses of epithelial cells are less than adipose cells, from which flows the fact that the radius of cancerous cells is generally less than for normal cells. The impact on the fractional volume of cancerous cells versus normal cells is that the fractional volume of cancerous cells is greater than for normal cells. The reason for this is that the epithelial population is higher than for normal, adipose cells. Finally, the intracellular conductivity of cancerous cells is greater than for intracellular conductivity of normal cells. Moreover, the extracellular conductivity is higher because of the abundance of extracellular fluid resulting from larger gaps between normal and cancerous cells. Thus, the conductivity of the infiltrated tissue will be greater than for normal tissue.
Various studies show that the values of biological tissues resistivities vary for a host of reasons. Cancerous tumors, for instance, possess two orders of magnitude (factor of 100) higher conductivity and permittivity values than surrounding healthy tissue. The application of medical treatments also produces a change in the electrical properties of tissue. For muscle tissue treated with radiation, measurable changes to tissue impedance are reported. Significant changes occur in electrical impedance of skeletal muscle at low frequencies during hyperthermia treatment, and this change of electrical properties foreshadows the onset of cell necrosis.
Electrical impedance tomography (EIT) is a process that maps the impedance distribution within an object. This map is typically created from the application of current and the measurement of potential differences along the boundary of that object. There are three categories of EIT systems: current injection devices, applied potential devices, and induction devices. Henderson and Webster first introduced a device known as the impedance camera that produced a general map of impedance distribution. The Sheffield System and its incarnations were the first generation EIT system. In the late 1980's, Li and Kruger report on an induced current device. In such a system, a combination of coils is placed around the object under test. A changing current in the coils produces a varying magnetic field that in turn induces a current in the object under test. As with the other drive method, electrodes are placed on the boundary of the object to measure the potential drops along the boundary.
Such electrical property imaging techniques are often referred to as “impedance tomography.” Most conventional electrical property imaging techniques are based on the premises that: 1) electrodes, or sensors, should be attached directly to the sample to be measured (for medical applications, the sample is a human body), and 2) current is injected sequentially through each electrode into the sample and the subsequent voltages measured. Therefore, these conventional EIT imaging techniques implement a “constant current/measured voltage” scheme.
In a departure from such conventional electrical property imaging techniques, U.S. Pat. No. 4,493,039 disclosed a method in which sensors are arranged in an array outside the object to be measured and during imaging of a sample, AC voltages are applied at a fixed amplitude while the current is measured. This approach, which is sometimes referred to as electrical property enhanced tomography (EPET), was further improved upon as described in U.S. Pat. No. 6,522,910 by filling the space between the object and the sensor array with an impedance matching medium.